Abstract The glutamatergic synapses are the main excitatory synapses in the brain. Abnormal synapse formation and plasticity are responsible for numerous diseases, such as intellectual disability, autism, neuropsychiatric and degenerative disorders. The signaling mechanisms controlling their assembly and plasticity have not been fully understood. Our preliminary studies lead to the surprising finding that components of the highly conserved cell polarity signaling pathways are important regulators. We found that components of both planar cell polarity (PCP) and apical-basal polarity (A-BP) pathways are localized in developing excitatory synapses and interact with multiple key presynaptic and postsynaptic proteins. In this proposal, we propose to test several hypotheses on how these key cell polarity components regulate glutamatergic synapse formation and plasticity. !